Quinazoline derivatives and methods of treatment

ABSTRACT

This invention relates to novel quinazoline derivatives, and their pharmaceutically acceptable salts. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions beneficially treated by inhibiting cell surface tyrosine receptor kinases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 60/875,320, filed Dec. 15, 2006, the contents of whichare incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

This invention relates to novel quinazoline derivatives, and theirpharmaceutically acceptable salts. The invention also providescompositions comprising a compound of this invention and the use of suchcompositions in methods of treating diseases and conditions beneficiallytreated by inhibiting cell surface tyrosine receptor kinases.

Quinazoline derivatives which bear at the 4-position an anilinosubstituent and which also bear an alkoxy substituent at the 7-positionand an alkoxy substituent at the 6-position, are disclosed at least inU.S. Pat. No. 5,747,498, EP 1,110,953, EP 817,775, and U.S. Pat. No.6,476,040. One of those derivatives, erlotinib, is known chemically as[6,7-Bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amineand as N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine.

Erlotinib is an inhibitor of tyrosine kinases, particularly EGF receptortyrosine kinases. Erlotinib has been approved in the United States inand in Europe for the treatment of locally advanced or metastaticnon-small cell lung cancer (NSCLC) after failure of at least one priorchemotherapy regimen. Erlotinib is also approved in the United States incombination with gemcitabine, for the treatment of metastatic pancreaticcancer. Clinical trials are ongoing investigating the use of erlotinibalone or in combination with other agents for the treatment of a varietyof cancers, including non-small cell lung cancer, ovarian cancer,colorectal cancer, head and neck cancer, brain cancer, bladder cancer,sarcoma, prostate cancer, melanoma, cervical cancer, solid tumors,astrocytoma, breast cancer, pancreatic cancer, glioblastoma multiform,renal cancer, digestive/gastrointestinal cancer, liver cancer, andgastric cancer. Erlotinib is also thought to be useful in the treatmentof benign hyperplasia of the skin (psoriasis) or prostate (BPH).

Despite the beneficial activities of erlotinib, there is a continuingneed for new compounds to treat the aforementioned diseases andconditions.

DEFINITIONS

The terms “ameliorate” and “treat” are used interchangeably and bothmean decrease, suppress, attenuate, diminish, arrest, or stabilize thedevelopment or progression of a disease (e.g., a disease or disorderdelineated herein).

By “disease” is meant any condition or disorder that damages orinterferes with the normal function of a cell, tissue, or organ.

It will be recognized that some variation of natural isotopic abundanceoccurs in a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. Thus, a preparation of erlotinib willinherently contain small amounts of deuterated and/or ¹³C-containingisotopologues. The concentration of naturally abundant stable hydrogenand carbon isotopes, notwithstanding this variation, is small andimmaterial with respect to the degree of stable isotopic substitution ofcompounds of this invention. See, for instance, Wada E et al., Seikagaku1994, 66:15; Ganes L Z et al., Comp Biochem Physiol Mol Integr Physiol1998, 119:725.

In a compound of this invention, when a particular position isdesignated as having deuterium, it is understood that the abundance ofdeuterium at that position is substantially greater than the naturalabundance of deuterium, which is 0.015%. A position designated as havingdeuterium typically has a minimum isotopic enrichment factor of at least3000 (45% deuterium incorporation) at each atom designated as deuteriumin said compound.

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope.

In other embodiments, a compound of this invention has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

In the compounds of this invention any atom not specifically designatedas a particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition.

In one embodiment, a compound of the invention contains less than 10%,preferably less than 6%, and more preferably less than 3% of all otherisotopologues combined, including a form that lacks any deuterium. Incertain aspects, the compound contains less than “X”% of all otherisotopologues combined, including a form that lacks any deuterium; whereX is any number between 0 and 10 (e.g., 1, 0.5, 0.001), inclusive.Compositions of matter that contain greater than 10% of all otherisotopologues combined are referred to herein as “mixtures” and mustmeet the parameters set forth below. These limits of isotopiccomposition and all references to isotopic composition herein, refersolely to the relative amounts of deuterium/hydrogen present in theactive, free base form of the compound of the formulae herein (e.g.,Formula I), and do not include the isotopic composition of hydrolyzableportions of prodrugs, or of counterions.

The term “isotopologue” refers to species that differ from a specificcompound of this invention only in the isotopic composition of theirmolecules or ions.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another preferred embodiment, the compound is apharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound or a prodrug of a compound of this invention. A“pharmaceutically acceptable counterion” is an ionic portion of a saltthat is not toxic when released from the salt upon administration to arecipient.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide, hydrochloric,hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well asorganic acids such as para-toluenesulfonic, salicylic, tartaric,bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic,formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic,lactic, oxalic, para-bromophenylsulfonic, carbonic, succinic, citric,benzoic and acetic acid, and related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephathalate, sulfonate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the likesalts. Preferred pharmaceutically acceptable acid addition salts includethose formed with mineral acids such as hydrochloric acid andhydrobromic acid, and especially those formed with organic acids such asmaleic acid.

The compounds of the present invention may contain one or moreasymmetric carbon atoms. As such, a compound of this invention can existas the individual stereoisomers (enantiomers or diastereomers) as well amixture of stereoisomers. Accordingly, a compound of the presentinvention will include not only a stereoisomeric mixture, but alsoindividual respective stereoisomers substantially free from one anotherstereoisomers. The term “substantially free of other stereoisomers” asused herein means less than 25% of other stereoisomers, preferably lessthan 10% of other stereoisomers, more preferably less than 5% of otherstereoisomers and most preferably less than 2% of other stereoisomers,or less than “X”% of other stereoisomers (wherein X is a number between0 and 100, inclusive) are present Methods of obtaining or synthesizingdiastereomers are well known in the art and may be applied aspracticable to final compounds or to starting material or intermediates.Other embodiments are those wherein the compound is an isolatedcompound. The term “at least X% enantiomerically enriched” as usedherein means that at least X% of the compound is a single enantiomericform, wherein X is a number between 0 and 100, inclusive.

The term “stable compounds”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintain theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., formulation into therapeuticproducts, intermediates for use in production of therapeutic compounds,isolatable or storable intermediate compounds, treating a disease orcondition responsive to therapeutic agents).

The terms “lighter isotopologue” and “lighter atom isotopologue” as usedherein, refer to species that differ from a specific compound of thisinvention in that they comprise hydrogen at positions occupied by adeuterium in the specific compound.

A specific compound of this invention may also be referred to as a“heavy atom isotopic compound” to distinguish it from its lighterisotopologues when discussing mixtures of isotopologues.

The term “heavy atom” refers to isotopes of higher atomic weight thanthe predominant naturally occurring isotope.

The term “stable heavy atom” refers to non-radioactive heavy atoms.

“D” refers to deuterium.

“Stereoisomer” refers to both enantiomers and diastereomers.

“Tert”, “^(t)”, and “t-” each refer to tertiary.

“US” refers to the United States of America.

“FDA” refers to Food and Drug Administration.

“NDA” refers to New Drug Application.

Throughout this specification, reference to “each Y” includes,independently, all “Y” groups (e.g., Y^(1a), Y^(1b), Y^(1c), Y^(2a),Y^(2b), and Y^(2c)) where applicable. Throughout this specification,reference to “each Z” includes, independently, all “Z” groups (e.g.,Z^(1a), Z^(1b), Z^(2a), and Z^(2b)) where applicable.

Therapeutic Compounds

In one embodiment, the present invention provides a compound of formulaI:

Formula I, or a pharmaceutically acceptable salt of said compound,wherein:

each Y (e.g., Y^(1a), Y^(1b), Y^(1c), Y^(2a), Y^(2b), and Y^(2c)) isindependently selected from hydrogen or deuterium;

each Z (e.g., Z^(1a), Z^(1b), Z^(2a), and Z^(2b)) is independentlyselected from hydrogen or deuterium;

and at least one Y or Z is deuterium.

In one embodiment, the invention provides a compound of formula I,wherein Y^(1a), Y^(1b), and Y^(1c) are simultaneously deuterium. Inanother embodiment, the invention provides a compound of formula I,wherein Y^(2a), Y^(2b) and Y^(2c) are simultaneously deuterium. In stillanother embodiment, the invention provides a compound of formula I,wherein Y^(1a), Y^(1b), Y^(1c), Y^(2a), Y^(2b) and Y^(2c) aresimultaneously deuterium.

In certain embodiments, the invention provides a compound of formula I,wherein each Z¹ is the same; and each Z² is the same.

In another embodiment, the invention provides a compound of formula I,wherein Z^(1a) and Z^(1b) are simultaneously deuterium.

In another embodiment, the invention provides a compound of formula I,wherein Z^(2a) and Z^(2b) are simultaneously deuterium.

In another embodiment, the invention provides a compound of formula I,wherein Z^(1a), Z^(1b), Z^(2a) and Z^(2b) are simultaneously deuterium.

Specific compounds of Formula I include those delineated in Table 1below.

TABLE 1 Cmpd Y^(1a) Y^(1b) Y^(1c) Y^(2a) Y^(2b) Y^(2c) Z^(1a) Z^(1b)Z^(2a) Z^(2b) 101 D D D H H H H H H H 102 H H H D D D H H H H 103 H H HH H H D D H H 104 H H H H H H H H D D 105 D D D D D D H H H H 106 H H HH H H D D D D 107 D D D H H H D D H H 108 H H H D D D H H D D 109 D D DD D D D D D D

In another embodiment, the invention provides a compound of Formula IA:

wherein each Y (e.g., Y^(1a), Y^(1b), Y^(1c), Y^(2a), Y^(2b), Y^(2c))and each Z (e.g., Z^(1a), Z^(1b), Z^(2a) and Z^(2b)) is independentlyselected from hydrogen and deuterium.

In one embodiment, the invention provides a compound of Formula IA,wherein each Y¹ is the same; and each Y² is the same. In one specificembodiment, Y^(1a), Y^(1b), and Y^(1c) are simultaneously deuterium. Inanother specific embodiment, Y^(2a), Y^(2b) and Y^(2c) aresimultaneously deuterium. In still another specific embodiment, Y^(1a),Y^(1b), Y^(1c), Y^(2a), Y^(2b) and Y^(2c) are simultaneously deuterium.

In certain embodiments, the invention provides a compound of Formula IA,wherein each Z¹ is the same; and each Z² is the same. In a specificembodiment Z^(1a) and Z^(1b) are simultaneously deuterium. In anotherspecific embodiment, Z^(2a) and Z^(2b) are simultaneously deuterium. Instill another specific embodiment, Z^(1a), Z^(1b), Z^(2a) and Z^(2b) aresimultaneously deuterium.

In still another specific embodiment of Formula IA, each Y and each Z issimultaneously hydrogen.

Specific compounds of Formula IA include those delineated in Table 1below.

TABLE 2 Cmpd Y^(1a) Y^(1b) Y^(1c) Y^(2a) Y^(2b) Y^(2c) Z^(1a) Z^(1b)Z^(2a) Z^(2b) W 110 H H H H H H H H H H D 111 D D D H H H H H H H D 112H H H D D D H H H H D 113 H H H H H H D D H H D 114 H H H H H H H H D DD 115 D D D D D D H H H H D 116 H H H H H H D D D D D 117 D D D H H H DD H H D 118 H H H D D D H H D D D 119 D D D D D D D D D D D

In another set of embodiments, any atom not designated as deuterium inany of the embodiments set forth above is present at its naturalisotopic abundance.

In an even more specific embodiment, the compound of this invention isselected from:

and

The synthesis of compounds of the formulae herein (e.g., Formula I andIA) can be readily effected by synthetic chemists of ordinary skill.Relevant procedures and intermediates are disclosed, for instance, inU.S. Pat. No. 5,747,498, EP 1,110,953, EP 817,775, and U.S. Pat. No.6,476,040. Such methods can be carried out utilizing correspondingdeuterated and optionally, other isotope-containing reagents and/orintermediates to synthesize the compounds delineated herein, or invokingstandard synthetic protocols known in the art for introducing isotopicatoms to a chemical structure.

Convenient methods for producing compounds of Formula I are described inSchemes 1-7. In each of the schemes set forth below, asterisks (*) areused to designate optional deuteration sites, each “P” is used todesignate an independently selected protecting group (e.g.,nitrogen-protecting group, tBOC, benzyl, acyl), and each “L” is used todesignate a displaceable group. A suitable displaceable group L is, forexample, a halogen, alkoxy, aryloxy or sulfonyloxy group, for example achloro, bromo, methoxy, phenoxy, methanesulfonyloxy ortoluene-4-sulfonyloxy group. Each R is an H, alkyl, alkoxyalkyl orprotecting group.

Scheme 1 shows the coupling of a quinazoline intermediate (II), with analkoxy intermediate (III), in the presence of a suitable base, such aspotassium carbonate, to form the compound of formula I. In alternateversions, the hydrogen atom on the aniline nitrogen of II may beoptionally replaced by a protecting group.

The compound II is synthesized by the reaction steps shown in Scheme 2.Quinazolinone IV is reacted with a compound of formula V in the presenceof heat, acid, or base, to form VI. Deprotection, if necessary, providesintermediate II. When R is an alkoxyalkyl, appropriate deprotection ofthe alkynyl P¹ provides compounds of formula I directly. Compound V canbe prepared from the corresponding nitro compound, by standard reduction(e.g., hydrogenation, H₂ gas with catalyst (e.g., 5% platinum onalumina), which can be prepared by alkyne-aryl coupling (e.g., palladium(II) mediated coupling of 1-bromo-3-nitrobenzene andtriethylsilylacetylene). See, for example U.S. Pat. No. 6,476,040.

Another synthetic route, based on the Dimroth rearrangement reaction (asreviewed, for example, by Wahren, M, Z Chem 1969, 9(7):241) is providedin Scheme 3. The process is advantageous in that it is convergent, andallows a substantial reduction in the number of intermediates that mustbe isolated. Additionally, chromatographic purification procedures arenot required. Elaboration of the R groups and the P¹ group on and/orprotection/deprotection is used to convert VIII to a compound of FormulaI.

Deprotection of the alkynyl P¹ group in any formulae herein (e.g.,Formula VIII) can be, for example, by treatment with an alkali metal oralkaline metal hydroxide where P¹ is —C(OH)dialkyl; or bytetraalkylammonium fluoride treatment where P¹ is trialkyl-(oralkyldiaryl-) silyl.

Scheme 4 shows an alternate route to a compound of Formula I, whereinthe dimethoxyquinazolinone 10 is demethylated to thedihydroxyquinazolinone 11 by heating in hydrobromic acid.Dihydroxyquinazolinone 11 is then acetylated with acetic anhydride toform the corresponding diacetylquinazolinone 12 which is halogenatedwith oxalyl chloride to form the chloroquinazoline 13. Chloroquinazoline13 is then combined with ethynyl aniline 17 to formdiacetylquinazolinamine 14. Deacetylation of diacetylquinazolinamine 14with ammonium hydroxide and methanol provides the correspondingquinazolinamine 15, which is then combined with an appropriatelydeuterated 2-methoxyethyl methane sulfonate 16 to form a compound ofFormula I.

Scheme 5 shows a synthetic route to compounds of Formula IA.Methyl-3,4-dihydroxy benzoate 18 is combined with an appropriatelydeuterated 2-methoxyethyl methane sulfonate 16 to produce intermediate19. Nitration of 19 with nitric acid and acetic acid produces thenitrobenzene compound 20. The nitrobenzene 19 is reduced to thecorresponding aniline 21, which is then cyclized to quinazolinone 22.The quinazolinone 22 is chlorinated with oxalyl chloride to form thechloroquinazoline 23, which is then combined with ethynyl aniline 17 toform a compound of Formula I. Conversion to a compound of Formula IA isachieved by treatment with isopropyl magnesium chloride in the presenceof d₃-MeOH and D₂O. This conversion step may be used on a compound ofFormula I produced by any of Schemes 1 to 4.

For the synthesis of compounds of the invention, a suitable base whennot specified is, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine, N-methylmorpholine ordiazabicyclo[5.4.0]undec-7-ene, or, for example, an alkali or alkalineearth metal carbonate or hydroxide, for example sodium carbonate,potassium carbonate, calcium carbonate, sodium hydroxide or potassiumhydroxide. Alternatively a suitable base is, for example, an alkalimetal or alkaline earth metal amide, for example sodium amide or sodiumbis(trimethylsilyl)amide.

All reactions are preferably carried out in the presence of a suitableinert solvent or diluent, which, if not specified is selected forexample from an aromatic solvent such as toluene, a xylene, cumene orchlorobenzene, an alkanol or ester such as methanol, ethanol,isopropanol or ethyl acetate, a halogenated solvent such as methylenechloride, chloroform or carbon tetrachloride, an ether such astetrahydrofuran or 1,4-dioxan, a polar aprotic solvent such asacetonitrile, propionitrile, butyronitrile, ethyl acetate,tetrahydrofuran or 1,4-dioxan, or a dipolar aprotic solvent such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-oneor dimethylsulfoxide. A further suitable solvent or diluent is water ora polar protic solvent such as a primary, secondary or tertiary alkylalcohol, for example, methanol, ethanol, a butanol or pentanol. Mixturesof such suitable solvents or diluents may be used.

If not specified, the reactions are conveniently carried out at atemperature in the range, for example, about 10° C. to about 250° C.,preferably in the range 20° C. to 100° C. In certain instances, thereaction temperature is the reflux temperature of the reaction solventor diluent or mixture thereof. For example, when the solvent or diluentis an aromatic solvent such as toluene, a xylene or cumene, or a mixturethereof, the reaction temperature is in the range, for example, 80 to250° C., conveniently in the range, for example, 100 to 170° C. or inthe range, for example, 100 to 140° C., more conveniently at or near110° C. or at or near 130° C. In the Dimroth reaction, a suitableelevated temperature is, for example, a temperature in the range, forexample, 40 to 250° C.

In one aspect of the invention, the rearrangement reaction is carriedout under substantially anhydrous conditions. In such a case, aconvenient solvent or diluent is, for example, an aromatic solvent suchas toluene or a xylene, or mixtures thereof.

If not otherwise indicated, the quinazoline derivative of the formula Imay be obtained from the processes set forth above in the form of thefree base or in the form of a salt with the acid of the formula H-Lwherein L has the meaning defined hereinbefore. When it is desired toobtain the free base from the salt, the salt may be treated with asuitable base as defined hereinbefore using a conventional procedure.Salts include but are not limited to, the hydrochloride salt,dihydrochloride salt, (+)-tartaric acid salt, difumaric acid salt,citric acid salt, dimethane sulfonic acid salt, disulfuric acid salt,and di-4-toluene sulfonic acid salt.

The specific approaches and compounds shown above are not intended to belimiting. The chemical structures in the schemes herein depict variablesthat are hereby defined commensurately with chemical group definitions(moieties, atoms, etc.) of the corresponding position in the compoundformulae herein, whether identified by the same variable name (i.e., R¹,R², R, R′, X, etc.) or not. The suitability of a chemical group in acompound structure for use in synthesis of another compound structure iswithin the knowledge of one of ordinary skill in the art.

Additional methods of synthesizing compounds of the formulae herein andtheir synthetic precursors, including those within routes not explicitlyshown in schemes herein, are within the means of chemists of ordinaryskill in the art. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe applicable compounds are known in the art and include, for example,those described in R. Larock, Comprehensive Organic Transformations, VCHPublishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley and Sons (1999); L. Fieser andM. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, JohnWiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagentsfor Organic Synthesis, John Wiley and Sons (1995) and subsequenteditions thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds.

The invention further provides a mixture of a compound of this inventionand its lighter isotopologues. These mixtures may occur, for instance,simply as the result of an inefficiency of incorporating the isotope ata given position; intentional or inadvertent exchange of protons fordeuterium, e.g. exchange of bulk solvent for heteroatom-attacheddeuterium; or intentional mixtures of pure compounds.

In one embodiment, such mixtures comprise at least about 50% of theheavy atom isotopic compound (i.e., less than about 50% of lighterisotopologues). More preferable is a mixture comprising at least 80% ofthe heavy atom isotopic compound. Most preferable is a mixturecomprising 90% of the heavy atom isotopic compound. In one aspect, is amixture at least about “X”% of the heavy atom isotopic compound (i.e.,less than about X% of lighter isotopologues), where X is a numberbetween 0 and 100, inclusive.

Compositions

The invention also provides compositions comprising an effective amountof a compound of the formulae herein (e.g., Formula I), or apharmaceutically acceptable salt, of said compound; and an acceptablecarrier. In one embodiment, the composition is a pyrogen-freecomposition. In another embodiment, a composition of this invention isformulated for pharmaceutical use (“a pharmaceutical composition”),wherein the carrier is a pharmaceutically acceptable carrier. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and, in the case of apharmaceutically acceptable carrier, not deleterious to the recipientthereof in amounts typically used in medicaments.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

If required, the solubility and bioavailability of the compounds of thepresent invention in pharmaceutical compositions may be enhanced bymethods well-known in the art. One method includes the use of lipidexcipients in the formulation. See “Oral Lipid-Based Formulations:Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs andthe Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare,2007; and “Role of Lipid Excipients in Modifying Oral and ParenteralDrug Delivery: Basic Principles and Biological Examples,” Kishor M.Wasan, ed. Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of anamorphous form of a compound of this invention optionally formulatedwith a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), orblock copolymers of ethylene oxide and propylene oxide. See U.S. Pat.No. 7,014,866; and United States patent publications 20060094744 and20060079502.

The pharmaceutical compositions of the invention include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. In certain embodiments, thecompound of the formulae herein is administered transdermally (e.g.,using a transdermal patch or iontophoretic techniques). Otherformulations may conveniently be presented in unit dosage form, e.g.,tablets and sustained release capsules, and in liposomes, and may beprepared by any methods well known in the art of pharmacy. See, forexample, Remington's Pharmaceutical Sciences, Mack Publishing Company,Philadelphia, Pa. (17th ed. 1985).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers or both, and then if necessary shaping theproduct.

In certain preferred embodiments, the compound is administered orally.Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion, or packed in liposomes and as a bolus,etc. Soft gelatin capsules can be useful for containing suchsuspensions, which may beneficially increase the rate of compoundabsorption.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be administered inthe form of suppositories for rectal administration. These compositionscan be prepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include, but are notlimited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art. See, e.g.: Rabinowitz J D and Zaffaroni A C, U.S. Pat. No.6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For applicationtopically to the skin, the pharmaceutical composition should beformulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches andiontophoretic administration are also included in this invention.

A specialized formulation for compounds of the formulae herein (e.g.,Formula I or IA) is a nanoparticulate formulation as disclosed forexample in WO 2006110811.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., (1966) Cancer Chemother Rep 50: 219. Body surface area may beapproximately determined from height and weight of the patient. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537.Effective doses will also vary, as recognized by those skilled in theart, depending on the diseases treated, the severity of the disease, theroute of administration, the sex, age and general health condition ofthe patient, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician.

The size of the dose required for the therapeutic or prophylactictreatment of a particular proliferative disease will necessarily bevaried depending on the subject treated, the route of administration,and the severity of the illness being treated. Such dosages can be foundin U.S. Pat. No. 5,770,599. The compounds of the invention will normallybe administered to a subject at a unit dose within the range of about 5mg to about 10,000 mg per square meter body area of the subject, i.e.from about 0.1 mg/kg to about 200 mg/kg, providing atherapeutically-effective dose. A unit dose form such as a tablet orcapsule will usually contain, for example from about 1 mg to about 250mg of active ingredient. Application of the subject therapeutics may belocal, so as to be administered at the site of interest. Varioustechniques can be used for providing the subject compositions at thesite of interest, such as injection, use of catheters, trocars,projectiles, pluronic gel, stents, sustained drug release polymers orother device which provides for internal access.

Thus, according to yet another embodiment, the compounds of thisinvention may be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents, or catheters. Suitable coatings and the generalpreparation of coated implantable devices are known in the art and areexemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccharides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics in thecomposition. Coatings for invasive devices are to be included within thedefinition of pharmaceutically acceptable carrier, adjuvant or vehicle,as those terms are used herein.

According to another embodiment, the invention provides a method ofcoating an implantable medical device comprising the step of contactingsaid device with the coating composition described above. It will beobvious to those skilled in the art that the coating of the device willoccur prior to implantation into a mammal.

According to another embodiment, the invention provides a method ofimpregnating an implantable drug release device comprising the step ofcontacting said drug release device with a compound or composition ofthis invention. Implantable drug release devices include, but are notlimited to, biodegradable polymer capsules or bullets, non-degradable,diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, the invention provides an implantablemedical device coated with a compound or a composition comprising acompound of this invention, such that said compound is therapeuticallyactive.

According to another embodiment, the invention provides an implantabledrug release device impregnated with or containing a compound or acomposition comprising a compound of this invention, such that saidcompound is released from said device and is therapeutically active.

Where an organ or tissue is accessible because of removal from thepatient, such organ or tissue may be bathed in a medium containing acomposition of this invention, a composition of this invention may bepainted onto the organ, or a composition of this invention may beapplied in any other convenient way.

In another embodiment, a composition of the present invention furthercomprises a second therapeutic agent. The second therapeutic agentincludes any compound or therapeutic agent known to have or thatdemonstrates advantageous properties when administered with erlotinib.Such agents are described in detail in U.S. Pat. No. 5,770,599; WO2001/076586; WO 2002/005791; WO 2001/070255; WO 2003/088971; WO2004/014426; WO 2005/000213; WO 2005/004872; WO 2005/046665; WO2005/052005; WO 2005/117888; WO 2006/026313; WO 2004/035057; and WO2006/099396; the disclosures of which are incorporated herein byreference.

In one embodiment, the second therapeutic agent is selected from2-deoxy-2-[18F]fluoro-D-glucose, 3′-deoxy-3′-[18F]fluorothymidine,5-fluorouracil, AV412, avastin, bevacizumab, bexarotene, bortezomib,calcitriol, canertinib, capecitabine, carboplatin, celecoxib, cetuximab,CHR-2797, cisplatin, dasatinib, digoxin, enzastaurin, etoposide,everolimus, fulvestrant, gefitinib, gemcitabine, genistein, imatinib,irinotecan, lapatinib, lenalidomide, letrozole, leucovorin, matuzumab,oxaliplatin, paclitaxel, panitumumab, pegfilgrastim, pegylatedalfa-interferon, pemetrexed, Polyphenon® E, satraplatin, sirolimus,sorafenib, sutent, sulindac, sunitinib, taxotere, temodar, temozolomide,temsirolimus, TG01, tipifarnib, trastuzumab, valproic acid, vinflunine,volociximab, vorinostat, and XL647.

In a more specific embodiment, the second therapeutic agent isbevacizumab.

In another embodiment, the invention provides separate dosage forms of acompound of this invention and one or more of any of the above-describedsecond therapeutic agents, wherein the compound and second therapeuticagent are associated with one another. The term “associated with oneanother” as used herein means that the separate dosage forms arepackaged together or otherwise attached to one another such that it isreadily apparent that the separate dosage forms are intended to be soldand administered together (within less than 24 hours of one another,consecutively or simultaneously).

In the pharmaceutical compositions of the invention, the compound of thepresent invention is present in an effective amount. As used herein, theterm “effective amount” refers to an amount which, when administered ina proper dosing regimen, is sufficient to reduce or ameliorate theseverity, duration or progression of the disorder being treated, preventthe advancement of the disorder being treated, cause the regression ofthe disorder being treated, or enhance or improve the prophylactic ortherapeutic effect(s) of another therapy.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., (1966) Cancer Chemother. Rep 50: 219. Body surface area may beapproximately determined from height and weight of the patient. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.

In one embodiment, an effective amount of a compound of this inventioncan range from a daily dose in the range of from about 1 mg/kg to about100 mg/kg is employed. In certain embodiments, a compound of theinvention or a pharmaceutically-acceptable salt thereof, will beadministered at a daily dose of about 1 mg/kg to about 20 mg/kg;preferably about 1 mg/kg to about 5 mg/kg is employed. In certainembodiments, a unit dose in the range of about 1 mg/kg to about 200mg/kg, preferably about 1 mg/kg to about 100 mg/kg, more preferablyabout 1 mg/kg to about 10 mg/kg, is envisaged.

Effective doses will also vary, as recognized by those skilled in theart, depending on the diseases treated, the severity of the disease, theroute of administration, the sex, age and general health condition ofthe patient, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician. For example, guidance for selecting an effectivedose can be determined by reference to the prescribing information forerlotinib.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 20% and 100% of the dosage normally utilized in a monotherapyregime using just that agent. Preferably, an effective amount is betweenabout 70% and 100% of the normal monotherapeutic dose. The normalmonotherapeutic dosages of these second therapeutic agents are wellknown in the art. See, e.g., Wells et al., eds., PharmacotherapyHandbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), each of which referencesare incorporated herein by reference in their entirety.

If the second therapeutic agents referenced above act synergisticallywith the compounds of this invention it will allow the effective dosageof the second therapeutic agent and/or the compound of this invention tobe reduced from that required in a monotherapy. This has the advantageof minimizing toxic side effects of either the second therapeutic agentof a compound of this invention, synergistic improvements in efficacy,improved ease of administration or use and/or reduced overall expense ofcompound preparation or formulation.

Methods of Treatment

According to another embodiment, the invention provides a method oftreating a subject suffering from or susceptible to a disease that isbeneficially treated by erlotinib comprising the step of administeringto the subject in need thereof an effective amount of a compound or acomposition of this invention. Such diseases are well known in the artand are disclosed, for example, in U.S. Pat. No. 5,770,599, U.S. Pat.No. 5,747,498, EP 1,110,953, EP 817,775, and U.S. Pat. No. 6,476,040. Inparticular, the invention provides a method of treating a subjectsuffering from or susceptible to cancer, inflammation, angiogenesis,vascular restenosis, immunological disorder, pancreatitis, kidneydisease, blastocyte maturation and implantation, psoriasis, or benignprostatic hypertrophy (BPH).

In a more specific embodiment, the cancer is selected from non-smallcell lung cancer, ovarian cancer, colorectal cancer, head and neckcancer, brain cancer, bladder cancer, sarcoma, prostate cancer,melanoma, cervical cancer, solid tumors, astrocytoma, breast cancer,pancreatic cancer, glioblastoma multiform, renal cancer,digestive/gastrointestinal cancer, liver cancer, and gastric cancer.

In an even more specific embodiment, the cancer is non-small cell lungcancer.

The compounds of the invention also have utility in the treatment ofadditional disorders of cellular growth in which aberrant cell signalingby way of receptor tyrosine kinase enzymes or non-receptor tyrosinekinase enzymes, including as yet unidentified tyrosine kinase enzymes,are involved. Such disorders include, for example, inflammation,angiogenesis, vascular restenosis, immunological disorder, pancreatitis,kidney disease and blastocyte maturation and implantation. Additionally,the compounds of the invention can be used to treat other diseasesinvolving excessive cellular proliferation such as psoriasis and benignprostatic hypertrophy (BPH).

Methods delineated herein include those wherein the subject isidentified as in need of a particular stated treatment. Identifying asubject in need of such treatment can be in the judgment of a subject ora health care professional and can be subjective (e.g. opinion) orobjective (e.g. measurable by a test or diagnostic method).

In another embodiment, any of the above methods of treatment comprisesthe further step of co-administering to the patient one or more secondtherapeutic agents. The choice of second therapeutic agent may be madefrom any second therapeutic agent known to be useful forco-administration with erlotinib. The choice of second therapeutic agentis also dependent upon the particular disease or condition to betreated. Examples of second therapeutic agents that may be employed inthe methods of this invention are those set forth above for use incombination compositions comprising a compound of this invention and asecond therapeutic agent.

In particular, the combination therapies of this invention include amethod of treating a patient suffering from or susceptible to cancercomprising the step of co-administering a compound of Formula I and asecond therapeutic agent selected from 2-deoxy-2-[18F]fluoro-D-glucose,3′-deoxy-3′-[18F]fluorothymidine, 5-fluorouracil, AV412, avastin,bevacizumab, bexarotene, bortezomib, calcitriol, canertinib,capecitabine, carboplatin, celecoxib, cetuximab, CHR-2797, cisplatin,dasatinib, digoxin, enzastaurin, etoposide, everolimus, fulvestrant,gefitinib, gemcitabine, genistein, imatinib, irinotecan, lapatinib,lenalidomide, letrozole, leucovorin, matuzumab, oxaliplatin, paclitaxel,panitumumab, pegfilgrastim, pegylated alfa-interferon, pemetrexed,Polyphenon® E, satraplatin, sirolimus, sorafenib, sutent, sulindac,sunitinib, taxotere, temodar, temozolomide, temsirolimus, TG01,tipifamib, trastuzumab, valproic acid, vinflunine, volociximab,vorinostat, and XL647 to the patient in need thereof.

In a more specific embodiment, the co-administered second therapeuticagent is bevacizumab.

In an even more specific embodiment, the co-administered secondtherapeutic agent is bevacizumab and the patient is suffering fromnon-small cell lung cancer.

The term “co-administered” as used herein means that the secondtherapeutic agent may be administered together with a compound of thisinvention as part of a single dosage form (such as a composition of thisinvention comprising a compound of the invention and an secondtherapeutic agent as described above) or as separate, multiple dosageforms. Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of a compound ofthis invention. In such combination therapy treatment, both thecompounds of this invention and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of this invention, comprising both a compound of theinvention and a second therapeutic agent, to a patient does not precludethe separate administration of that same therapeutic agent, any othersecond therapeutic agent or any compound of this invention to saidpatient at another time during a course of treatment.

Effective amounts of these second therapeutic agents are well known tothose skilled in the art and guidance for dosing may be found in patentsand published patent applications referenced herein, as well as in Wellset al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),and other medical texts. However, it is well within the skilledartisan's purview to determine the second therapeutic agent's optimaleffective-amount range.

In one embodiment of the invention, where a second therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount would be where the secondtherapeutic agent is not administered. In another embodiment, theeffective amount of the second therapeutic agent is less than itseffective amount would be where the compound of this invention is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art.

In another aspect, the invention provides the use of a compound of theformulae herein, or a pharmaceutically-acceptable salt thereof, in themanufacture of a medicament for use in the production of ananti-proliferative effect in a subject.

In another embodiment, the invention provides a method of modulating theactivity of cell surface tyrosine receptor kinases, including epidermalgrowth factor receptor kinases (EGFR), in a cell comprising contactingthe cell with one or more compounds of any of the formulae herein.

In yet another aspect, the invention provides the use of a compound ofthe formulae herein (e.g., Formula I or IA) alone or together with oneor more of the above-described second therapeutic agents in themanufacture of a medicament, either as a single composition or asseparate dosage forms, for treatment or prevention in a subject of adisease, disorder or symptom set forth above. Another aspect of theinvention is a compound of the formulae herein for use in the treatmentor prevention in a subject of a disease, disorder or symptom thereofdelineated herein.

Diagnostic Methods and Kits

The compounds and compositions of this invention are also useful asreagents in methods for determining the concentration of erlotinib insolution or biological sample such as plasma, examining the metabolismof erlotinib and other analytical studies.

According to one embodiment, the invention provides a method ofdetermining the concentration, in a solution or a biological sample, oferlotinib, comprising the steps of:

adding a known concentration of a compound of Formula I or IA to thesolution of biological sample;

subjecting the solution or biological sample to a measuring device thatdistinguishes erlotinib from a compound of Formula I or IA;

calibrating the measuring device to correlate the detected quantity ofthe compound of Formula I or IA with the known concentration of thecompound of Formula I or IA added to the biological sample or solution;and

measuring the quantity of erlotinib in the biological sample with saidcalibrated measuring device; and

determining the concentration of erlotinib in the solution of sampleusing the correlation between detected quantity and concentrationobtained for a compound of Formula I or IA.

Measuring devices that can distinguish erlotinib from the correspondingcompound of Formula I or IA include any measuring device that candistinguish between two compounds that differ from one another only inisotopic abundance. Exemplary measuring devices include a massspectrometer, NMR spectrometer, or IR spectrometer.

In another embodiment, the invention provides a method of evaluating themetabolic stability of a compound of Formula I or IA comprising thesteps of contacting the compound of Formula I or IA with a metabolizingenzyme source for a period of time and comparing the amount of thecompound of Formula I or IA with the metabolic products of the compoundof Formula I or IA after the period of time.

In a related embodiment, the invention provides a method of evaluatingthe metabolic stability of a compound of Formula I or IA in a patientfollowing administration of the compound of Formula I or IA. This methodcomprises the steps of obtaining a serum, urine or feces sample from thepatient at a period of time following the administration of the compoundof Formula I or IA to the subject; and comparing the amount of thecompound of Formula I or IA with the metabolic products of the compoundof Formula I or IA in the serum, urine or feces sample.

The present invention also provides kits for use to treat non-small celllung cancer, ovarian cancer, colorectal cancer, head and neck cancer,brain cancer, bladder cancer, sarcoma, prostate cancer, melanoma,cervical cancer, solid tumors, astrocytoma, breast cancer, pancreaticcancer, glioblastoma multiform, renal cancer, digestive/gastrointestinalcancer, liver cancer, or gastric cancer. These kits comprise (a) apharmaceutical composition comprising a compound of Formula I or IA or apharmaceutically acceptable salt thereof, wherein said pharmaceuticalcomposition is in a container; and (b) instructions describing a methodof using the pharmaceutical composition to treat the cancer.

The container may be any vessel or other sealed or sealable apparatusthat can hold said pharmaceutical composition. Examples include bottles,ampules, divided or multi-chambered holders bottles, wherein eachdivision or chamber comprises a single dose of said composition, adivided foil packet wherein each division comprises a single dose ofsaid composition, or a dispenser that dispenses single doses of saidcomposition. The container can be in any conventional shape or form asknown in the art which is made of a pharmaceutically acceptablematerial, for example a paper or cardboard box, a glass or plasticbottle or jar, a re-sealable bag (for example, to hold a “refill” oftablets for placement into a different container), or a blister packwith individual doses for pressing out of the pack according to atherapeutic schedule. The container employed can depend on the exactdosage form involved, for example a conventional cardboard box would notgenerally be used to hold a liquid suspension. It is feasible that morethan one container can be used together in a single package to market asingle dosage form. For example, tablets may be contained in a bottle,which is in turn contained within a box. In one embodiment, thecontainer is a blister pack.

The kits of this invention may also comprise a device to administer orto measure out a unit dose of the pharmaceutical composition. Suchdevice may include an inhaler if said composition is an inhalablecomposition; a syringe and needle if said composition is an injectablecomposition; a syringe, spoon, pump, or a vessel with or without volumemarkings if said composition is an oral liquid composition; or any othermeasuring or delivery device appropriate to the dosage formulation ofthe composition present in the kit.

In certain embodiment, the kits of this invention may comprise in aseparate vessel of container a pharmaceutical composition comprising asecond therapeutic agent, such as one of those listed above for use forco-administration with a compound of this invention.

EXAMPLES Example 1 Synthesis of 2-d₃-methoxyethyl methane sulfonate 16

Reagent 16 is prepared according to the following Scheme.

Synthesis of 2-(2-bromoethoxy)tetrahydro-2H-pyran (25). To a solution of2-bromoethanol 24 (50.0 g, 40 mmol) in methylene chloride (500 mL)cooled to 0° C. was added 3,4-dihydro-2H-pyran (40.32 g, 48 mmol)followed by p-TSA.H₂O (100 mg) was added. Reaction mixture was stirredat 0° C. for 5.0 h. The reaction mixture was washed with aq NaHCO₃ andbrine, dried over Na₂SO₄ and evaporated to give the product 25 (75.0 g,90%). This crude product was taken to next step without purification.

Synthesis of 2-(2-d₃-methoxyethoxy)tetrahydro-2H-pyran (26). To asolution of 2-(2-bromoethoxy)tetrahydro-2H-pyran, 25 (40.0 g, 24.3 mmol)in DMF (100 mL) was added K₂CO₃ (40.24 g, 48.0 mmol) and CD₃I (4.23 g,29.2 mmol) and stirred at 60° C. for 12.0 h. The reaction mixture waspoured into cold water and extracted with diethyl ether (2×150 mL).Combined organic extracts were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure to give the product 26 (11.50 g,37%).

Synthesis of 2-d₃-methoxy ethanol (27). To a solution of2-(2-d₃-methoxyethoxy)tetrahydro-2H-pyran, 26 (11.0 g, 6.77 mmol) inmethanol (25 mL) was added p-TSA.H₂O (100 mg). The resulting mixture wasstirred at room temperature for 10.0 h. Methanol was distilled atatmospheric pressure and the residue was distilled at 140° C. to givethe 2-d₃-methoxy ethanol, 27 (3.00 g, 57%).

Synthesis of 2-d₃-methoxyethyl methane sulfonate (16). To a 0° C. cooledsolution of 2-d₃-methoxyethanol, 27 (2.80 g, 36.8 mmol) and triethylamine (4.80 mL) in methylene chloride (50 mL) was added methanesulfonylchloride (4.10 g, 37 mmol) was added and stirred at 0° C. for2.0 h. The reaction mixture was washed with aq NaHCO₃ and brine, driedover Na₂SO₄ and concentrated under reduced pressure to give the product(3.05 g, 55%). ¹H NMR (CDCl₃): 2.94 (s, 3H), 3.66 (m, 2H), 3.80 (t, 2H).

Example 2N-(3-ethynylphenyl)-6,7-bis(2-d₆-methoxyethoxy)quinazolin-4-aminehydrochloride

Compound 105 is prepared according to Scheme 4 above.

Synthesis of 6,7-dihydroxy-4(3H)-quinazolinone (11). To6,7-dimethoxy-4(3H)-quinazolinone, 10 (3.0 g, 14.5 mmol) was added 48%HBr (36 mL) and the solution was heated to reflux at 100° C. for 12 h.The reaction mixture was cooled to room temperature and the solids werefiltered. The solid obtained was neutralized with aq. NH₃ (pH=8) and thesolution was filtered and washed with water and dried to give6,7-dihydroxy-4(3H)-quinazolinone, 11 as a off-white crystalline solid(2.20 g, 84%).

Synthesis of 6,7-diacetoxy-4(3H)-quinazolinone (12). To6,7-dihydroxy-4(3H)-quinazolinone, 11 (2.20 g, 12.2 mmol) was added Ac₂O(13.3 ml) and a drop of pyridine and the reaction mixture was heated toreflux at 120° C. for 2 h. The reaction mixture was cooled to roomtemperature and the solvent was distilled off under reduced pressure.The residue was taken up in water and stirred for an hour at roomtemperature. The solid obtained was filtered and dried to give6,7-diacetoxy-4(3H)-quinazolinone 12 as an off-white crystalline solid(1.70 g, 53%).

Synthesis of 4-chloroquinazoline-6,7-diyl diacetate (13). To a solutionof 6,7-diacetoxy-4(3H)-quinazolinone, 12 (3.20 g, 11.42 mmol) in CHCl₃(60 ml) was added oxalyl chloride (2.2 ml, 17.3 mmol) dropwise at 0° C.The resulting reaction mixture was stirred at room temperature for 15minutes then was gradually heated to reflux for 5 h during which timethe starting material was consumed. The reaction mixture was cooled to10° C. and the solution was quenched with aq sodium bicarbonate. Theorganic layer was separated and washed with brine then dried over Na₂SO₄and directly taken to the next step without concentration.

Synthesis of N-(3-ethynylphenyl)-6,7-diacetoxy-4-quinazolinaminehydrochloride (14). To the organic layer of the previous step was addedethynyl aniline 17 (1.19 ml, 11.42 mmol) and the reaction mixture washeated to reflux overnight. The reaction mixture was cooled to roomtemperature and the solution was filtered to giveN-(3-ethynylphenyl)-6,7-diacetoxy-4-quinazolinamine hydrochloride, 14 asa solid (3.0 g, 94%).

Synthesis of N-(3-ethynylphenyl)-6,7-dihydroxy-4-quinazolinaminehydrochloride (15). To the hydrochloride salt, 14 (4.2 g, 11.62 mmol) inmethanol (30 ml) was added 25% aqueous ammonia (4.73 ml) and thesolution was stirred for 4 h. The reaction mass was filtered and thesolid was washed with water to give theN-(3-ethynylphenyl)-6,7-dihydroxy-4-quinazolinamine hydrochloride, 15(3.0 g, 93%) as a brownish yellow solid. ¹H NMR (400 MHz, DMSO-d₆): 4.2(s, 1H), 7.10 (s, 1H), 7.17-7.19 (m, 2H), 7.34-7.39 (t, 1H), 7.79 (s,1H), 7.87-7.89 (d, 1H), 8.05 (s, 1H), 8.45 (s, 1H), 9.4-9.6 (bs. s, 1H).MS (ESI): 278.

Synthesis ofN-(3-ethynylphenyl)-6,7-bis(2-d₆-methoxyethoxy)quinazolin-4-aminehydrochloride (Compound 105). A solution ofN-(3-ethynylphenyl)-6,7-dihydroxy-4-quinazolinamine 15 (250 mg, 0.89mmol), 2-d₃-methoxyethyl methane sulfonate 16 (0.83 g, 5.34 mmol), andcesium carbonate (1.70 g, 5.34 mmol) in DMF (10 mL) was heated to 60° C.for 12 h. The reaction mixture was cooled to room temperature and pouredinto cold water, extracted with ethyl acetate (2×20 mL) and the combinedorganic layer were washed with water and brine, dried over Na₂SO₄ andconcentrated to give Compound 105 (150 mg). MS (ESI): 400.

Example 3 Synthesis of N-(3-di-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine hydrochloride (Compound 110)

Compound 110 was synthesized according to Scheme 5 above.

Synthesis of methyl 3,4-bis(2-methoxyethoxy)benzoate (19). A solution ofmethyl 3,4-dihydroxybenzoate (18, 10.0 g, 64.88 mmol), 2-methoxyethylmethane sulfonate 16 (59.95 g, 389.3 mmol), potassium carbonate (54.06g, 389.30 mmol), sodium iodide (58.35 g, 389.3 mmol) in DMF (100 mL) washeated to 100° C. Reaction progress was monitored by TLC and after 12.0h the reaction was found to be complete. The reaction mixture was cooledto room temperature and poured in to cold water. Extracted with ethylacetate (2×150 mL) and the combined organic layer were washed with waterand brine. Dried over Na₂SO₄ and evaporated to give compound 19.

Synthesis of methyl 3,4-bis(2-methoxyethoxy)benzoate (20). To a solutionof compound 19 (17.0 g, 59.79 mmol) in acetic acid (57.8 mL) was addeddropwise nitric acid (18.3 mL, 70%) at 0-5° C. and this mixture wasstirred at room temperature. Reaction was monitored by HPLC @254 nm andafter 10.0 h the reaction was complete. Reaction mixture was poured oncold water (100 mL) and extracted with ethyl acetate (3×150 mL). Thecombined organic extracts were washed with aq NaHCO₃ (2×100 mL) andbrine. Dried over Na₂SO₄ and evaporated to give compound 20.

Synthesis of methyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate (21). Asolution of compound 20 (17.0 g, 51.62 mmol) in ethanol (150 mL) wasadded 10% Pd—C (1.70 g) and subjected to hydrogenation in a parrapparatus (50 psi) at room temperature. Reaction was monitored by TLC.After 12.0 h TLC indicated no starting material. The catalyst wasfiltered off by using a celite plug and washed with ethanol (50 mL).Solvent was removed was removed under reduced pressure to affordcompound 21 as brown slurry

Synthesis of 6,7-bis(2-methoxyethoxy)quinazolin-4(3H)-one (22).Formamide (130 mL) was added to a solution of compound 21 (13.0 g, 43.43mmol) in N-methyl-2-pyrrolidone (130 mL) and the reaction mixture washeated to 165-170° C. under N₂ for 12 h. Reaction was monitored by TLC.After 8.0 h TLC indicated no starting material. The reaction mixture waspoured in to ice cold water and solids were filtered. The crude productwas purified by column chromatography to give compound 22 as lightyellow solid.

Synthesis of 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline (23). To asolution of compound 22 (2.60 g, 8.83 mmol) in dichloromethane (25 mL),was added a drop of N,N-Dimethyl formamide and to that oxalyl chloride(1.52 mL, 17.669 mmol) was added dropwise. This mixture was stirred atroom temperature for 12 h. Reaction was monitored by TLC and thereduction continued until TLC indicated no starting material. Thereaction mixture was poured in to water. Extracted with ethyl acetateand the combined organic layer were washed with Sat.NaHCO₃ and brine anddried over Na₂SO₄ and evaporated to give the crude compound 23 (3.5 g,crude), which was used in the next reaction without furtherpurification.

Synthesis ofN-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib).A solution of compound 23 (3.5 g, 11.19 mmol) in isopropanol (20 mL) wasadded drop wise to a solution of pyridine (0.71 mL, 8.95 mmol) and4-ethynylphenylamine (1.17 mL, 11.19 mmol) in isopropanol (50 mL).Reaction mixture was stirred and heated to reflux under argon resultingin precipitation of orange solid. Then the reaction mixture brought toroom temperature and stirred 12.0 h. The precipitate was filtered andwashed with hot isopropanol and dried to yield erlotinib (1.66 g, 35%).¹H NMR (DMSO-d₆): 3.36 (s, 6H), 3.78 (s, 4H), 4.30 (s, 1H), 4.35 (t,4H), 7.40 (d, 1H), 7.50 (t, 1H), 7.36 (d, 1H), 7.87 (s, 1H), 8.33 (s,1H), 8.85 (s, 1H), 11.30 (s, 1H). MS: MS: ESI, m/z 394[M+H]⁺. HPLC:98.9% (@254 nm).

Synthesis ofN-(3-di-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(Compound 110). To a −30° C. cooled solution of erlotinib (250 mg, 0.90mmol) in THF (20 L) was added isopropyl magnesium chloride (1.6 N inTHF, 2 mL). Reaction mixture was stirred at −30° C. for 3.0 h and CD₃OD(1 mL) was added and slowly brought to room temperature over a period of2.0 h. Stirred at room temperature and reaction was monitored by MS.After 10.0 h MS showed 3% starting material. Reaction mixture wasquenched with D₂O and extracted with ethyl acetate (2×25 mL). Combinedorganic extracts were washed with water and brine. Dried over Na₂SO₄ andevaporated to give Compound 110 (178 mg, 76%).

Example 4 Metabolism Studies

Certain in vitro liver metabolism studies have been described previouslyin the following references, each of which is incorporated herein intheir entirety: Obach, R S, Drug Metab Disp, 1999, 27:1350; Houston, J Bet al., Drug Metab Rev, 1997, 29:891; Houston, JB, Biochem Pharmacol,1994, 47:1469; Iwatsubo, T et al., Pharmacol Ther, 1997, 73:147; andLave, T, et al., Pharm Res, 1997, 14:152.

Microsomal Assay. The metabolic stability of compounds of Formula I orIA is tested using pooled liver microsomal incubations. Full scan LC-MSanalysis is then performed to detect major metabolites. Samples of thetest compounds, exposed to pooled human liver microsomes, are analyzedusing HPLC-MS (or MS/MS) detection. For determining metabolic stability,multiple reaction monitoring (MRM) is used to measure the disappearanceof the test compounds. For metabolite detection, Q1 full scans are usedas survey scans to detect the major metabolites.

Experimental Procedures. Human liver microsomes are obtained from acommercial source (e.g., XenoTech, LLC (Lenexa, Kans.)). The incubationmixtures are prepared as follows:

Reaction Mixture Composition Liver Microsomes 0.5-2.0 mg/mL NADPH 1 mMPotassium Phosphate, pH 7.4 100 mM Magnesium Chloride 10 mM TestCompound 0.1-1 μM.

Incubation of Test Compounds with Liver Microsomes. The reactionmixture, minus cofactors, is prepared. An aliquot of the reactionmixture (without cofactors) is incubated in a shaking water bath at 37°C. for 3 minutes. Another aliquot of the reaction mixture is prepared asthe negative control. The test compound is added into both the reactionmixture and the negative control at a final concentration of 1 μM. Analiquot of the reaction mixture is prepared as a blank control, by theaddition of plain organic solvent (not the test compound). The reactionis initiated by the addition of cofactors (not into the negativecontrols), and then incubated in a shaking water bath at 37° C. Aliquots(200 μL) are withdrawn in triplicate at multiple time points (e.g., 0,15, 30, 60, and 120 minutes) and combined with 800 μL of ice-cold 50/50acetonitrile/dH₂O to terminate the reaction. The positive controls,testosterone and propranolol, as well as erlotinib, are each runsimultaneously with the test compounds in separate reactions.

All samples are analyzed using LC-MS (or MS/MS). An LC-MRM-MS/MS methodis used for metabolic stability. Also, Q1 full scan LC-MS methods areperformed on the blank matrix and the test compound incubation samples.The Q1 scans serve as survey scans to identify any sample unique peaksthat might represent the possible metabolites. The masses of thesepotential metabolites can be determined from the Q1 scans.

SUPERSOMES™ Assay. Various human cytochrome P450-specific SUPERSOMES™are purchased from Gentest (Woburn, Mass., USA). A 1.0 mL reactionmixture containing 25 pmole of SUPERSOMES™, 2.0 mM NADPH, 3.0 mM MgCl,and 1 μM of a compound of Formula I or IA or II in 100 mM potassiumphosphate buffer (pH 7.4) was incubated at 37° C. in triplicate.Positive controls contain 1 μM of erlotinib instead of a compound ofFormula I or IA. Negative controls used Control Insect Cell Cytosol(insect cell microsomes that lacked any human metabolic enzyme)purchased from GenTest (Woburn, Mass., USA). Aliquots (50 μL) areremoved from each sample and placed in wells of a multi-well plate atvarious time points (e.g., 0, 2, 5, 7, 12, 20, and 30 minutes) and toeach aliquot is added 50 μL of ice cold acetonitrile with 3 μMhaloperidol as an internal standard to stop the reaction.

Plates containing the removed aliquots are placed in −20° C. freezer for15 minutes to cool. After cooling, 100 μL of deionized water is added toall wells in the plate. Plates are then spun in the centrifuge for 10minutes at 3000 rpm. A portion of the supernatant (100 μL) is thenremoved, placed in a new plate and analyzed using Mass Spectrometry.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of the present invention andpractice the claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. It will be apparent to those of ordinary skill inthe art that various modifications and equivalents can be made withoutdeparting from the spirit and scope of the invention.

1. The compound

or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1, wherein any atom not designated as deuterium is present at itsnatural isotopic abundance.
 3. A pyrogen-free composition comprising thecompound of claim 1, and an acceptable carrier.
 4. The composition ofclaim 3 formulated for pharmaceutical administration, wherein thecarrier is a pharmaceutically acceptable carrier.
 5. A method oftreating a patient suffering from psoriasis, the method comprising thestep of administering to the patient a composition of claim
 4. 6. Amethod of treating a patient suffering from a disease or disorderselected from non-small cell lung cancer, ovarian cancer, colorectalcancer, head and neck cancer, brain cancer, bladder cancer, sarcoma,prostate cancer, melanoma, cervical cancer, solid tumors, astrocytoma,breast cancer, pancreatic cancer, glioblastoma multiform, renal cancer,digestive/gastrointestinal cancer, and liver cancer, the methodcomprising the step of administering to the patient a composition ofclaim
 4. 7. The method of claim 6, wherein the patient is suffering fromnon-small cell lung cancer.
 8. The method of claim 5, comprising thefurther step of co-administering to the patient in need thereof a secondtherapeutic agent useful in the treatment of a disease or disorderselected from cancer, inflammation, angiogenesis, vascular restenosis,immunological disorder, pancreatitis, kidney disease, blastocytematuration and implantation, psoriasis, and benign prostatic hypertrophy(BPH).
 9. The method of claim 8, wherein the patient is suffering fromcancer and the second therapeutic agent is selected from2-deoxy-2-[¹⁸F]fluoro-D-glucose, 3′-deoxy-3′-[¹⁸F]fluorothymidine,5-fluorouracil, AV412, avastin, bevacizumab, bexarotene, bortezomib,calcitriol, canertinib, capecitabine, carboplatin, celecoxib, cetuximab,CHR-2797, cisplatin, dasatinib, digoxin, enzastaurin, etoposide,everolimus, fulvestrant, gefitinib, gemcitabine, genistein, imatinib,irinotecan, lapatinib, lenalidomide, letrozole, leucovorin, matuzumab,oxaliplatin, paclitaxel, panitumumab, pegfilgrastim, pegylatedalfa-interferon, pemetrexed, satraplatin, sirolimus, sorafenib, sutent,sulindac, sunitinib, taxotere, temodar, temozolomide, temsirolimus,TG01, tipifarnib, trastuzumab, valproic acid, vinflunine, volociximab,vorinostat, and XL647.
 10. The method of claim 9, wherein the secondtherapeutic agent is bevacizumab.
 11. The method of claim 10, whereinthe patient is suffering from non-small cell lung cancer.
 12. Thecompound of claim 1, wherein each designated deuterium atom of thecompound has an isotopic enrichment factor of at least 3000.